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RemeOs science and clinical evidence

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RemeOs™
Magnesium Alloy Mg-Ca-Zn
Material Science and Clinical
evidence
Revision 1.0 / 2023/11/27
RemeOs™ Screw is the first healthy
and absorbable metal implant in the
U.S market
2
Bioretec
RemeOs™ Screw LAG Solid
Definitions
• Biomaterial = A natural or synthetic material that is suitable for introduction into living tissue.
• Bioactivity = The ability of a material to interact with or effect any cell tissue in the human body. The ability of a
material to form a direct bond with the host biological tissue
• Biocompatibility = The ability of a material to perform with an appropriate host response in a specific situation.
The ability of a material to be in contact with a living system without producing an adverse effect.
• Osteointegration = The property of a material that allows the development of a direct, adherent and strong bond
with the surrounding bone tissue. The formation of a direct interface between an implant and bone, without
intervening soft tissue.
• Osteoconduction = The ability of a material to facilitate new bone formation by allowing bone cells to adhere,
proliferate, and form an extracellular matrix on its surface and pores. Primarily based on mechanical stimuli as well
as the chemical composition and geometry of the material.
• Osteopromotion = Describes a material that promotes the de novo formation of bone and needs an osseous
defect that provides nutrients (blood) to enhance bone growth. Effectively promotes new bone growth by
accelerating bone remodeling.
• Osteoinduction = The ability to induce new bone formation through molecular stimuli recruitment and
differentiation in a controlled phenotype or particular lineage promote cellular functions leading to new bone
formation
3
RemeOs™ material Science
Bone/Fracture healing
RemeOs™ material Science
• The central goal of any fracture treatment is to
restore bone continuity, thereby reinstating the
function of the affected extremity or body section
and alleviating pain1,2.
• A critical aspect in terms of orthopedic implants
is that they should not impede the natural
physiology of the bone healing process.
• Bone is a living tissue capable of self-repair
• Bone only forms when mechanical loading is
present and constantly adjusts itself in response to
physiological and mechanical changes(Wolff’s
law).3,4
• Bone is continuously being renewed; balance
between osteoblasts forming bone and osteoclasts
resorbing bone.5
• This process of constant bone resorption and bone
formation is called bone remodeling
• Osteoclasts break down and remove old and damaged
bone, whereas osteoblasts deposit new bone matrix that
subsequently becomes mineralized.
• Rebuilding bone following a fracture can be classified into
primary (direct) and secondary (indirect) healing.1
• Secondary (indirect) healing occurs in the vast majority of bone
injuries. It is typically characterized by distinct but overlapping stages:
a) hematoma formation and inflammation, b-c) repair, and d)
remodeling.
Following these initial phases, a
soft callus (fibrocartilaginous
callus) forms from the
granulation tissue
approximately 2–3 weeks after
fracture. When the fracture
ends are bridged by a soft
callus, Ca is deposited, leading
to the development of a hard
callus or woven bone. This hard
callus stage might persist for
about 12–16 weeks.
Damaged blood vessels
immediately lead to a
hematoma formation at
the fracture site, which is
gradually replaced during
the inflammatory phase
by fibrin rich granulation
tissue at 3–7 days post-
fracture. Osteoclasts start
to resorb the necrotic
bone at the fracture ends.
In the last step of fracture
repair, bone remodeling,
small bone fragments are
removed by osteoclasts,
while osteoblasts deposit
woven bone and then
convert it to lamellar bone.
Adapted from ref 2.
4
Magnesium in general
• Mg is well-suitable as a biodegradable implant material.
• It is an essential element for the human body and the fourth most
abundant cation (Mg2+) 6,7, with approximately 20–28 g in a healthy
adult human body8,9. About half of the total amount is stored within
the skeleton and positively influences bone strength10. Less than one
percent is found in the blood11. The remaining portion is bound in the
muscles and soft tissue. It plays a major role in membrane
stabilization, neuromuscular excitation, and central nervous system
functions12. It acts as a cofactor in almost all enzymatic systems,
stabilizes structures like DNA or RNA, and is involved in metabolic
pathways13.
• Excessive Mg ions are permissible as they can be transported via the
circulatory system and promptly excreted by way of urine and faces,
without causing any adverse effects.14
• Published studies suggest that the exposure of bone to a
degrading Mg implant exerts a positive impact on the biological
process of bone growth and regeneration. This is attributed to
locally high amounts of available Mg and stimulatory effects
such as osteoblastic differentiation, which in turn promotes
bone formation15-18. Mg ions integrate into the apatite crystal
lattice, enhancing cell adhesion and accelerating the growth of
bone tissue19-20.
5
RemeOs™ material Science
Daily dietary intake
360mg
Daily urinary output
100mg
Daily faecal output
260mg
INTESTINE
Absorption 120mg
Secretion 20mg
KIDNEY
Filtration 2400mg
Reabsorption 2300mg
BLOOD
COMPARTMENT
OTHER TISSUES
4900mg
MUSCLE
6600mg
Bone
12900mg
Adopted from ref 21.
RemeOs™ Magnesium alloy (Mg-Ca-Zn)
• Pure Mg is relatively weak and is almost exclusively used as an alloy for engineering and medical applications.22
• Material properties of Mg alloys can be adjusted by different alloying elements. With appropriate alloying elements,
the mechanical, physical, and electrochemical (degradation rate) properties can be improved and adapted, like
enhancing yield strength, ductility and controlling gas evolution.
• In terms of biomedical products, the choice of alloying elements is limited as the resulting by-products should exert
minimal effects on the body, must be non-toxic, and must be capable of either being absorbed by surrounding tissues
or dissolved and excreted naturally.23,24
• RemeOs™ alloying elements yielding together with Magnesium yield a HEALTHY implant :
• Calcium: Ca is a promising alloying element for absorbable Mg alloys due to its biocompatibility arising from its natural occurrence
within the human metabolism. It positively influences bone health and can help to accelerate growth and healing25,26. It has been
reported that Ca enhances both the mechanical properties and the corrosion resistance of Mg-based alloys27,28. The addition of Ca to
a Mg alloy results in grain refinement28,29, which is an effective method to enhance the strength by grain boundary hardening,
described by the Hall-Patch relationship30,31. Another notable advantage of Ca is its influence on elevated ductility26,32.
• Zinc: The yield strength of Mg alloys can be enhanced by adding Zn due to grain refinement33-35. One advantageous aspect of Zn as
an alloying element is its potential to decrease the amount of hydrogen gas evolution resulting from Mg corrosion24,36. Zn has been
observed to enhance osteoblastic cell proliferation and positively influence bone healing when used as an alloying element in Mg-
based biomaterials. Generally, Zn enhances the corrosion resistance of Mg alloys, but the effect varies based on the specific alloy
composition26.
6
RemeOs™ material Science

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RemeOs science and clinical evidence

  • 1. RemeOs™ Magnesium Alloy Mg-Ca-Zn Material Science and Clinical evidence Revision 1.0 / 2023/11/27
  • 2. RemeOs™ Screw is the first healthy and absorbable metal implant in the U.S market 2 Bioretec RemeOs™ Screw LAG Solid
  • 3. Definitions • Biomaterial = A natural or synthetic material that is suitable for introduction into living tissue. • Bioactivity = The ability of a material to interact with or effect any cell tissue in the human body. The ability of a material to form a direct bond with the host biological tissue • Biocompatibility = The ability of a material to perform with an appropriate host response in a specific situation. The ability of a material to be in contact with a living system without producing an adverse effect. • Osteointegration = The property of a material that allows the development of a direct, adherent and strong bond with the surrounding bone tissue. The formation of a direct interface between an implant and bone, without intervening soft tissue. • Osteoconduction = The ability of a material to facilitate new bone formation by allowing bone cells to adhere, proliferate, and form an extracellular matrix on its surface and pores. Primarily based on mechanical stimuli as well as the chemical composition and geometry of the material. • Osteopromotion = Describes a material that promotes the de novo formation of bone and needs an osseous defect that provides nutrients (blood) to enhance bone growth. Effectively promotes new bone growth by accelerating bone remodeling. • Osteoinduction = The ability to induce new bone formation through molecular stimuli recruitment and differentiation in a controlled phenotype or particular lineage promote cellular functions leading to new bone formation 3 RemeOs™ material Science
  • 4. Bone/Fracture healing RemeOs™ material Science • The central goal of any fracture treatment is to restore bone continuity, thereby reinstating the function of the affected extremity or body section and alleviating pain1,2. • A critical aspect in terms of orthopedic implants is that they should not impede the natural physiology of the bone healing process. • Bone is a living tissue capable of self-repair • Bone only forms when mechanical loading is present and constantly adjusts itself in response to physiological and mechanical changes(Wolff’s law).3,4 • Bone is continuously being renewed; balance between osteoblasts forming bone and osteoclasts resorbing bone.5 • This process of constant bone resorption and bone formation is called bone remodeling • Osteoclasts break down and remove old and damaged bone, whereas osteoblasts deposit new bone matrix that subsequently becomes mineralized. • Rebuilding bone following a fracture can be classified into primary (direct) and secondary (indirect) healing.1 • Secondary (indirect) healing occurs in the vast majority of bone injuries. It is typically characterized by distinct but overlapping stages: a) hematoma formation and inflammation, b-c) repair, and d) remodeling. Following these initial phases, a soft callus (fibrocartilaginous callus) forms from the granulation tissue approximately 2–3 weeks after fracture. When the fracture ends are bridged by a soft callus, Ca is deposited, leading to the development of a hard callus or woven bone. This hard callus stage might persist for about 12–16 weeks. Damaged blood vessels immediately lead to a hematoma formation at the fracture site, which is gradually replaced during the inflammatory phase by fibrin rich granulation tissue at 3–7 days post- fracture. Osteoclasts start to resorb the necrotic bone at the fracture ends. In the last step of fracture repair, bone remodeling, small bone fragments are removed by osteoclasts, while osteoblasts deposit woven bone and then convert it to lamellar bone. Adapted from ref 2. 4
  • 5. Magnesium in general • Mg is well-suitable as a biodegradable implant material. • It is an essential element for the human body and the fourth most abundant cation (Mg2+) 6,7, with approximately 20–28 g in a healthy adult human body8,9. About half of the total amount is stored within the skeleton and positively influences bone strength10. Less than one percent is found in the blood11. The remaining portion is bound in the muscles and soft tissue. It plays a major role in membrane stabilization, neuromuscular excitation, and central nervous system functions12. It acts as a cofactor in almost all enzymatic systems, stabilizes structures like DNA or RNA, and is involved in metabolic pathways13. • Excessive Mg ions are permissible as they can be transported via the circulatory system and promptly excreted by way of urine and faces, without causing any adverse effects.14 • Published studies suggest that the exposure of bone to a degrading Mg implant exerts a positive impact on the biological process of bone growth and regeneration. This is attributed to locally high amounts of available Mg and stimulatory effects such as osteoblastic differentiation, which in turn promotes bone formation15-18. Mg ions integrate into the apatite crystal lattice, enhancing cell adhesion and accelerating the growth of bone tissue19-20. 5 RemeOs™ material Science Daily dietary intake 360mg Daily urinary output 100mg Daily faecal output 260mg INTESTINE Absorption 120mg Secretion 20mg KIDNEY Filtration 2400mg Reabsorption 2300mg BLOOD COMPARTMENT OTHER TISSUES 4900mg MUSCLE 6600mg Bone 12900mg Adopted from ref 21.
  • 6. RemeOs™ Magnesium alloy (Mg-Ca-Zn) • Pure Mg is relatively weak and is almost exclusively used as an alloy for engineering and medical applications.22 • Material properties of Mg alloys can be adjusted by different alloying elements. With appropriate alloying elements, the mechanical, physical, and electrochemical (degradation rate) properties can be improved and adapted, like enhancing yield strength, ductility and controlling gas evolution. • In terms of biomedical products, the choice of alloying elements is limited as the resulting by-products should exert minimal effects on the body, must be non-toxic, and must be capable of either being absorbed by surrounding tissues or dissolved and excreted naturally.23,24 • RemeOs™ alloying elements yielding together with Magnesium yield a HEALTHY implant : • Calcium: Ca is a promising alloying element for absorbable Mg alloys due to its biocompatibility arising from its natural occurrence within the human metabolism. It positively influences bone health and can help to accelerate growth and healing25,26. It has been reported that Ca enhances both the mechanical properties and the corrosion resistance of Mg-based alloys27,28. The addition of Ca to a Mg alloy results in grain refinement28,29, which is an effective method to enhance the strength by grain boundary hardening, described by the Hall-Patch relationship30,31. Another notable advantage of Ca is its influence on elevated ductility26,32. • Zinc: The yield strength of Mg alloys can be enhanced by adding Zn due to grain refinement33-35. One advantageous aspect of Zn as an alloying element is its potential to decrease the amount of hydrogen gas evolution resulting from Mg corrosion24,36. Zn has been observed to enhance osteoblastic cell proliferation and positively influence bone healing when used as an alloying element in Mg- based biomaterials. Generally, Zn enhances the corrosion resistance of Mg alloys, but the effect varies based on the specific alloy composition26. 6 RemeOs™ material Science
  • 7. RemeOs™ bioactive and osteopromotive implants are Mg alloy optimized to support bone healing • RemeOs™ Magnesium – Calcium – Zinc alloy has been designed to have a controlled degradation rate through its composition with controlled impurity profile (Cu, Ni, Fe, Zr, and heavy metals) and manufacturing process, yielding high mechanical properties • RemeOs™ alloy has a nominal content of Ca 0.55 w-%, Zn 0.45 w-% with Mg composing the rest • Only with this proprietary composition, Ca is able to form Mg2Ca intermetallic precipitates, which act as a sacrificial anode, protecting Mg-matrix from excess corrosion • Biomechanical properties are closer to bone (cortical) than traditional metals, biopolymers, and composites • Biomechanical properties have been designed to retain strength over the bone healing period without stress shielding and which gradually diminishes through surface degradation to allow bone to gain its natural strength 7 RemeOs™ material Science One drawback of classic non- degradable metals (Ti, SS) is their mismatch in mechanical properties to bone. Bones need mechanical stress produced by everyday movements to become ossified, retain their strength, and regenerate (Wollf’s Law)3,4. Metallic implants are notably stiffer, with a Young’s modulus of about 100–200 GPa as opposed to 10–30 GPa for the human bone37,38. This difference can cause stress shielding, where the stiffer implant mechanically shields the bone tissue from loading stresses. This effect can cause bone atrophy and osteolysis39-41, resulting in altered bone morphology42 and a general delay in the healing process39.
  • 8. Degradation of Magnesium alloy • The mechanism of the degradation (absorption) of magnesium and its alloys is a complex multifactorial phenomenon depending on various parameters like geometry, mechanical and chemical composition (nature and ratio of alloying elements), and interactions with the physiological environment • Pure Mg is one of the most electronegative engineering materials, possessing a low standard potential of -2.37 V 43,44. Therefore, it is highly susceptible to degradation in various environments, including the physiological conditions within the body 45,46. The degradation process of Mg is an electrochemical process in the aqueous environment • The degradation (absorption) proceeds electrochemically as follows: The anodically initiated Mg dissolution occurs according to Equation (1). This counterbalances the cathodic reaction, wherein the hydrogen gas develops (Equation (2)). The product formation of Mg(OH)2 proceeds electrochemically according to Equation (3).47 Mg → Mg+ 2e− (1) 2H2O + 2e − → H2 + 2OH− (2) Mg2+ + 2OH− → Mg(OH)2 (3) • The total degradation (absorption) reaction of Mg in aqueous environments can be given, in which Mg(OH)2 forms a protective layer around the implant while hydrogen gas (H2) is produced (4).47 Mg(s) + 2H2O(aq) → Mg(OH)2(s) + H2(g) (4) • To meet the requirement of a medical implant, degradation (absorption) resistance must be enhanced by adding alloying elements to slow down the degradation rate and increase implant stability. 8 RemeOs™ material Science
  • 9. Degradation of Magnesium alloy • The presence of inorganic salts in the physiological solutions of the human body increases the complexity of the degradation of Magnesium alloys. • The degradation of magnesium alloys forms a degradation zone on top of the magnesium alloy implant in accordance with the following chemical reactions.47 Mg(s) + 2H2O(aq) → Mg(OH)2(s) + H2(g) OH- + HCO3 - → CO3 2- + H2O Mg2+ + CO3 2- → MgCO3 (s) H2PO4 - / HPO4 2- + OH- → PO4 3- + H20 3Mg2+ + 2PO4 3- → Mg3 (PO4)2 (s) Ca2+ + CO3 2- → CaCO3 (s) 3Ca2+ + 2PO4 3- → Ca3(PO4)2 (s) • The main intermediate product deposits on the degradation zone are Mg(OH)2, MgCO3, Mg3(PO4)2, CaCO3, and Ca3(PO4)2.48,49 9 RemeOs™ material Science The degradation zone at a pH value of approximately 7.4 (in vivo conditions) is neither stable nor complete and will continuously be dissolved50 but forms a bioactive hydroxy apatite (HA) layer for cells to attach. Mg2+ H2 Mg(OH)2 H2O HCO3- CO3 2- Ca2+ PO4 3- Hydroxy apatite layer HA Ca3(PO4)2 Mg3(PO4)2 CaCO3 Physiological conditions Biomineralization MgCO3 Mg alloy implant
  • 10. Verification of degradation zone in Mg-Ca-Zn • The Mg-doped Calcium and Phosphorous rich hydroxyapatite layer HA (degradation zone) is formed due to the degrading implant and has been examined using SEM-EDX (rat, 24 weeks) in a sample cross-section. • The SEM image shows the morphology of the bone-implant interface, and the black rectangle outlines the interfacial region of investigation for EDX. • The elemental profile was measured from top to bottom along the dashed line (top, left panel), indicating the presence of the degradation zone as Mg/O-rich. • It shows a gradual increase in Ca and P levels toward the bone. I. denotes the implant region, II. corresponds to the initial degradation layer, III. designates the second layer in the degradation zone referred to as the direct bone-implant interface, and IV. represents the bone tissue. 10 RemeOs™ material Science Mg is represented in yellow, O in purple, Ca in pink, and P in green. Adopted from ref 51.
  • 11. Biological interface • Mg alloys have been defined as a type of biomaterial that have osteopromotive52 effects due to their degradation products. • Studies have shown that Mg degradation products can enhance osteogenesis, inhibit catabolic activity and osteoclast differentiation, and promote osteoblast adhesion and motility to facilitate bone recovery • Mg2+ stimulates the osteogenic differentiation of stem cells with selective activation of the MAPK/ERK pathway53. The MAPK/ERK pathway is one of the signaling pathways governing the osteogenic differentiation of stem cells. • Mg2+ enhances the mineralization of the extracellular matrix (ECM) by increasing the production of collagen-X and vascular endothelial growth factor (VEGF).54 • The high concentration of Mg2+ and high pH, reduces the fusion of pre-osteoclast cells and the activity of osteoclasts, thereby inhibiting osteoclastogenesis.55 • Vessel development is vital for bone formation, and Mg2+ can promote angiogenesis by stimulating VEGF, angiogenin and other crucial chemoattractants.56 • Mg plays a multifunctional role in bone growth and regeneration. It exerts both direct and indirect effects between connecting bone, vessels, nerves, and immune systems, creating potential for functional bone regeneration.51 RemeOs™ material Science Degradation zone / Mg- Doped HA layer Mg alloy implant Periosteum Cortical Bone Trabecular Bone Medullary Cavity Periosteal stem cells (PSCs) Bone marrow stem cells (BMSCs) Differentiation Differentiation Osteoblast-like cells Osteoblast-like cells Osteoclast Pre-osteoclast Monocytes of vascular/ bone marrow origin Migration along bone surface Migration along trabeculae High Mg2+ reduces cell fusion High pH reduces resorption Mg2+ concentration The effects of Mg in the biological interface have been comprehensively investigated using both in vitro and in vivo models 57-60
  • 12. Osteopromotion of RemeOs Mg alloy In Vivo Enhanced bone growth verified in large animal studies • Strong new bone growth (callus formation) was observed as early as 6 weeks, and in 12 weeks, the RemeOs™ screw was overgrown with new bone (green circle) • No biological activity within the Titanium control group at the 6 weeks or 12 weeks timepoint (orange circle) • The corrosion behavior of low-alloyed Mg-Ca-Zn is characterized by a slow and controlled homogenous degradation. Furthermore, implants showed excellent biocompatibility, new bone formation, and established a robust implant-bone interface.61 12 RemeOs™ material Science 6 weeks 12 weeks RemeOs™ Titanium
  • 13. Long term large animal study in large animal shows osteointegration and homogeneous resorption 13 RemeOs™ material Science Long-term 2 years large animal study in sheep of Mg-Ca-Zn 3.5 mm screw shows surface resorption and new bone formation. 62 Total degradation time depends on the screw size (surface degradation), complete resorption is around 2-3 years. (A-C) Histologic evaluation of the 24-mm ZX00 screw after the 25-month period in sheep tibiae with (D) respective micro-CT. 62 (A) New bone formation, “bony bridges,” within the medullary cavity is marked with a black arrow, and reactive woven bone formation on the periosteum adjacent to the screw head is marked with a white asterisk. (B) Osteocytes and osteoblasts are marked with black and white arrowheads, respectively. (C) The fat necrosis area is shown with white arrows, and gas pockets are marked with black asterisks (Laczko-Levai stain; original magnification, x10).
  • 14. The Role of degradation product H2 • Degradation within the aqueous environment of the body is highly complex. Controlling the degradation rate is challenging and plays a fundamental role in bone formation. The actual corrosion rate in the body varies depending on several factors, like the pH of body fluids, the concentration and types of ions present, the presence of proteins, temperature, impurities in the metal, alloying elements, and the surrounding tissue. • The process of Mg degradation is always accompanied by hydrogen gas evolution, and the rate of gas formation directly depends on the degradation rate of the alloy. • The role of degradation products H2 in the biological interface is not completely clear. Thus, H2 plays a significant role in the regulation of the local microenvironment and the biology of resident cells and may inhibit osteoclast formation.63 • It has been postulated that a slow hydrogen evolution rate of 0.01 ml/cm2/day could be tolerated by the body painlessly without causing severe harm if the gas can be transported away from the site of its generation.22 • If the local hydrogen saturation of blood and tissue is reached, diffusion and solubility of hydrogen in surrounding tissues become hindered. Then hydrogen gas can accumulate and create gas voids in the tissue around the implantation site. • Therefore, adjusting the degradation rate, and consequently the rate of gas accumulation, through appropriate alloying elements is essential. 14 RemeOs™ material Science Schematic description of the degradation process and H2 avolution under in vitro conditions. a) electrochemical reactions, b) absorption-desorption process, c) mass transfer processes, d) precipitation reactions, e) complexation reactions, f) acid-base reactions
  • 15. Degradation zone and H2 gas evolution 28/11/23 15 RemeOs™ material Science OP 2 weeks 6 weeks 12 weeks 24 weeks Degradation zone and H2 gas evolution The preclinical and clinical studies have shown that the degradation zone build-up and gas evolution start immediately after the implantation and are most prominent during first few weeks and start to slow down after 6 weeks, and start to decrease at 12 weeks, with the fracture healed after 6 weeks (no visible fracture line in 12- & 24-weeks time points)62,64,65 Fracture healing
  • 16. In vivo strength retention over healing period 16 RemeOs™ material Science 12weeks 6 weeks 0 weeks • Strength retention over 12 weeks in vivo has been demonstrated in a large animal model with no statistical difference between implantation and 12 weeks pullout force (p = 0.08, ⍶ = 0.05) • No effect of degradation products (including H2) on the strength retention • According to the in vitro – in vivo (IVIVC) correlation, 12 weeks in large animals corresponds to min 30 weeks in human high resolution micro-computed tomography In Vivo Pull-out testing in large animal model Data on File
  • 17. RemeOs™ screw Surgical technique & MRI compatibility • Surgical technique similar to conventional metal implants • Self-tapping and easy insertion • Compression performance and fixation strength comparable to conventional metal implants • X-rays, CT or MRI can be used to evaluate the healing of the tissue. • The implants are MR Conditional. Imaging may demonstrate implant-associated radiolucent areas related to device absorption (hydrogen gas formation). Based on the MGAS Clinical Study, these abnormalities typically begin to decrease) at around 12 weeks and are not clinically significant. (FDA Instructions for use: BIORETEC RemeOs™ Screw LAG Solid IFU Rev. 1.0 2023-05-05) • Malleolar Fracture Fixation (typically 2 screws) 17 RemeOs™ material Science Drill the K-wire into the bone to keep the fracture in position and to mark the prescribed path for the cannulated screw. Countersink (optional). Use the countersink to make space for the screw head and to avoid soft tissue irritation from the protruding screw head. Drill a screw channel through the fracture plane using the appropriate drill bit. Irrigate prior to screw insertion to flush out bone debris. Hold the screwdriver and the screw parallel to the long axis of the drill hole and insert the screw fully into the drill hole.
  • 18. Safety and Efficacy of absorbable metal verified in clinical trial 18 RemeOs™ material Science ◼ Indication: Medial malleolar fracture fixation ◼ Patient enrollment: 20 patients through 12 weeks follow- up, 18 patients up to 130 weeks follow-up All primary end points achieved 62,64,65 ◼ In 6 weeks, 90% of the fractures were healed ◼ After 12 weeks complete consolidation in all patients ◼ No adverse events or intraoperative complications ◼ All patients regained mobility in the ankle joint ◼ No pain in any of the patients after 6 weeks ◼ Normal levels of Mg and Ca in blood ◼ Normal wound healing; no swelling, erythema, oedema nor infections ◼ No loosening of the implant nor clinical implications due to the H2 gas evolution OUTCOME: Fractures stabilized and healed in all patients Patients with medial malleolar fractures: pre-operative to after surgery Of the patients who also received Titanium implants, 71% of the Titanium hardware had to be removed Female, 47y Male, 30y Female, 64y
  • 19. Degradation zone in patient radiographs RemeOs™ material Science PRE-OP WEEK 2 WEEK 6 WEEK 12 WEEK 24 WEEK 52 WEEK 130 Female, 47y RemeOsTM screw visible (blue arrow) Degradation zone including gas evolution (white arrow) The syndesmosis screw was removed at week 6, and its hole (orange arrow) is visible in the cortex after week 130 Full absorption of the screw at week 130.
  • 20. Hole from Titanium syndesmosis screw Removal (removed at 6 week timepoint) Although radiographs revealed a homogeneous bone texture, CT slices revealed gaps at the Mg-Zn-Ca screw site in the trabecular bone, which may be because of recent resorption that has not been remodeled yet and may only be resolved with a longer bone remodeling period62. Bone only forms where it is needed when mechanical loading is present (Wolff’s law).3,4 Male, 30 years old, 130 weeks Full degradation within 130 weeks and ongoing bone remodeling RemeOs™ material Science 20 CT slice video
  • 21. FDA confirmed benefits of RemeOs™ trauma screw and material* 21 RemeOs™ material Science Excellent biocompatibility = Safe Bioactive, osteopromotive properties = Enhanced bone growth Fixation strength comparable with conventional metal implants = No screw loosening due to gas evolution The RemeOsTM bioresorbable metal is composed of natural elements found in the human body Magnesium (Mg), Calcium (Ca) and Zinc (Zn) Easy insertion and use, comparable to conventional metal implants = Common surgical techniques Rapid bone ingrowth, regeneration, and replacement = Makes removal operations redundant Strength retention tailored to match the bone healing = Carries the load over the healing period In this release the term (bio)resorbable is interchangeable with (bio)absorbable and (bio)degradable * RemeOs™ Risk analysis in FDA granted De Novo request
  • 22. FDA De Novo decision – The First RemeOs™ indication is for the Ankle and Foot area 22 RemeOs™ material Science DEVICE DESCRIPTION*: The implants are constructed of an absorbable magnesium-based alloy containing magnesium, zinc and calcium. The material is composed of natural elements found in the human body (Mg alloy with a nominal content of Ca 0.55 w-% and Zn 0.45 w-%). The material corrodes under physiological conditions into magnesium, calcium and zinc oxides and hydroxides, which are naturally occurring elements and compounds in the human body and are known to promote new bone growth. Hydrogen gas, which is a byproduct of the corrosion process, may contribute to transient bone lucency that is radiographically observable. The material has high initial mechanical strength and stiffness. Implants made from this material have similar biomechanical characteristics (E modulus, tensile strength) to those of natural (cortical) bone. When properly used, in the presence of adequate immobilization, the implants maintain accurate alignment of medial malleolus fractures, and osteotomies, after surgical procedure. INTENDED USE: RemeOs™ Screw LAG Solid is intended for the use in traumatic and orthopedic surgery for the fixation of bone fractures (osteosynthesis) and for the fixation after osteotomies, e.g., for the correction of deformities or malalignments. The absorbable implants serve as temporary fixation and stabilization by osteosynthesis of bone fractures and osteotomies until bony fusion has occurred. The RemeOs™ Screw LAG Solid is intended to be used for skeletally mature adults. INDICATED USE: The RemeOs™ Screw LAG Solid is indicated for the fixation of the medial malleolus. * *FDA approved instructions for use (IFU) In this release the term (bio)resorbable is interchangeable with (bio)absorbable and (bio)degradable
  • 23. Clinical application of Mg based absorbable metal for fracture fixation in the adult skeleton Patients with a full set of X-rays (pre-op, 2, 6, 12, 24, 52, 130 weeks follow-up) Data on File (Clinical Trial)
  • 24. 24 OP 6w 2W 24w 12w 52w 130w Female, 47 years old Male, 30 years old OP 6w 2W 24w 12w 52w 130w Female, 64 years old OP 6w 2W 24w 12w 52w 130w
  • 25. 25 Male, 43 years old OP 6w 2W 24w 12w 52w 130w OP 6w 2W 24w 12w 52w 130w Male, 46 years old Male, 29 years old OP 6w 2W 24w 12w 52w 130w
  • 26. 26 OP 6w 2W 24w 12w 52w 130w Male, 56 years old Male, 35 years old OP 6w 2W 24w 12w 52w 130w Female, 45 years old OP 6w 2W 24w 12w 52w 130w
  • 28. 28 2 weeks Male, 30 years old
  • 29. 29 6 weeks Male, 30 years old
  • 30. 30 12 weeks Male, 30 years old
  • 31. 31 20 weeks, CT scan Male, 30 years old
  • 32. 32 24 weeks Male, 30 years old
  • 33. 33 52 weeks Male, 30 years old
  • 35. 35 CT scan Video Removal hole of Titanium syndesmosis screw (removed at 6 week) Although radiographs revealed a homogeneous bone texture, CT slices revealed gaps at the implant site in the trabecular bone, which may be because of recent resorption that has not been remodeled yet and may only be resolved with a longer bone remodeling period. 62 130 weeks, CT scan Male, 30 years old
  • 37. 37 2 weeks Female, 47 years old Female, 47 years old
  • 38. 38 6 weeks Female, 47 years old Female, 47 years old
  • 39. 39 12 weeks Female, 47 years old Female, 47 years old
  • 40. 40 24 weeks Female, 47 years old Female, 47 years old
  • 42. 42 130 weeks Female, 47 years old Female, 47 years old
  • 43. 43 Male, 46 years old OP OP
  • 44. 44 Male, 46 years old 2 weeks
  • 45. 45 Male, 46 years old 6 weeks
  • 46. 46 Male, 46 years old 12 weeks
  • 47. 47 Male, 46 years old 24 weeks
  • 48. 48 Male, 46 years old 52 weeks
  • 49. 49 Male, 46 years old 64 weeks
  • 50. 50 Male, 46 years old 130 weeks
  • 52. 52 Female, 64 years old 2 weeks
  • 53. 53 Female, 64 years old 6 weeks
  • 54. 54 Female, 64 years old 12 weeks
  • 55. 55 Female, 64 years old 24 weeks
  • 56. 56 Female, 64 years old 52 weeks
  • 57. 57 Female, 64 years old 130 weeks
  • 59. 59 Male, 43 years old 2 weeks
  • 60. 60 Male, 43 years old 6 weeks
  • 61. 61 Male, 43 years old 12 weeks
  • 62. 62 Male, 43 years old 24 weeks
  • 63. 63 Male, 43 years old 52 weeks
  • 64. 64 Male, 43 years old 130 weeks
  • 66. 66 Male, 29 years old 2 weeks
  • 67. 67 Male, 29 years old 6 weeks
  • 68. 68 Male, 29 years old 12 weeks
  • 69. 69 Male, 29 years old 24 weeks
  • 70. 70 Male, 29 years old 52 weeks
  • 71. 71 Male, 29 years old 130 weeks
  • 73. 73 Male, 56 years old 2 weeks
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  • 75. 75 Male, 56 years old 12 weeks
  • 76. 76 Male, 56 years old 24 weeks
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  • 78. 78 Male, 56 years old 130 weeks
  • 80. 80 Female, 45 years old 2 weeks
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  • 83. 83 Female, 45 years old 24 weeks
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  • 85. 85 Female, 45 years old 130 weeks
  • 87. 87 Male, 35 years old 2 weeks
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  • 90. 90 Male, 35 years old 24 weeks
  • 91. 91 Male, 35 years old 52 weeks
  • 92. 92 Male, 35 years old 130 weeks
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